Any questions regarding the safety of tranexamic acid in patients undergoing cardiac surgery seem to have been put to rest with the ATACAS (Aspirin and Tranexamic Acid For Coronary Artery Surgery) trial. In a cohort of nearly 5,000 patients, the trial concluded that tranexamic acid was associated with a lower risk for bleeding than placebo, without a higher risk for death or thrombotic complications during the first 30 postoperative days.
“There are risk factors involved in any type of surgery, but particularly with cardiac surgery, where there are concerns regarding excessive bleeding and the association between the need for blood transfusion and postoperative complications,” said Paul S. Myles, MD, professor of anesthesia and perioperative medicine at Alfred Hospital and Monash University, in Melbourne, Australia.
“In cardiac surgery, there’s a particular concern with surgical reexploration, which comes at significant additional cost as well.”
For these reasons, antithrombotic therapies are used routinely now in most cardiac settings around the world. “The residual concern has always been that since these drugs reduce bleeding, do they increase thrombotic risk along the way?” Dr. Myles asked.
“There have been quite a few smaller studies and case reports giving the signal that this was indeed possible—particularly myocardial infarction and stroke in patients receiving these agents.”
To gain a better understanding of these possible relationships, researchers in Canada, England, Italy, Australia, New Zealand and Hong Kong enrolled 4,662 patients into the trial; data were available for 4,631. “This was very much an international trial, including 31 sites in several countries around the world,” Dr. Myles noted.
Focus: Death and Thrombotic Complications
The participants—all of whom were scheduled to undergo coronary artery surgery and were at risk for perioperative complications—were randomly assigned to receive a relatively high dose of tranexamic acid (100 mg/kg) prior to bypass (n=2,311) or placebo (n=2,320).
“The anesthesiologist was not always blinded to the treatment,” Dr. Myles said, “but certainly the patients, surgeons and follow-up staff were blinded to the assignment.” The study’s primary outcome was a composite of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure or bowel infarction) within 30 days of surgery.
Interestingly, the researchers found that a change in regimen was necessary during the trial period. “During the conduct of the trial, there seemed to be reports of a strong association between tranexamic acid in cardiac surgery and postoperative seizure events,” Dr. Myles said.
“It became apparent that this was likely dose-related. As such, our steering committee decided to change the tranexamic acid dose from 100 to 50 mg/kg.”
As Dr. Myles reported at the Major Trials Session of the American Society of Anesthesiologists’ 2016 annual meeting, a primary outcome event occurred in 386 patients (16.7%) in the tranexamic acid group and 420 patients (18.1%) in the placebo group (relative risk, 0.92; 95% CI, 0.81-1.05; P=0.22). Perhaps not surprisingly, patients in the tranexamic group received significantly fewer transfused units of blood products during hospitalization (4,331 units) than their counterparts in the placebo group (7,994 units; P<0.001).
“Our analysis showed that the tranexamic acid group received 46% fewer units of blood than those in the placebo group throughout their entire hospital stay,” Dr. Myles said. “The number needed to treat to prevent a blood transfusion was only six in patients undergoing coronary artery surgery.”
The findings also showed that major hemorrhage or cardiac tamponade leading to reoperation occurred in 1.4% of tranexamic acid patients and 2.8% of those receiving placebo (P=0.001).
“We quite clearly showed that there’s a 50% reduction in the risk of reoperation when you use tranexamic acid at the dose we used in the study,” he said. “The number needed to treat to prevent one patient needing a reoperation is 71, which we believe to be clinically impressive.”
Seizures occurred in 0.7% of tranexamic acid patients and 0.1% of placebo patients (P=0.002). “This is perhaps the first trial to ever test for the risk of seizures in this patient population,” Dr. Myles said. “We were able to demonstrate that it’s true: There is, in fact, an increased risk of seizures with tranexamic acid. That’s obviously an important finding in and of itself.”
Given the size of the trial, the researchers also were able to conduct various subgroup analyses, with equally compelling findings. “When we looked at a host of potential risk factors—whether they’re age factors or demographic risk factors, on-pump or off-pump surgery, other medications, baseline kidney function or bleeding factors—there is no particular subgroup effect that would suggest the findings would be any different in any such population.
“Bear in mind that this is also a large multicenter trial with many sites in many countries,” he added. “And even by country, we found no specific treatment effect.”
The researchers included an analysis of cost savings based solely on blood transfusions. The analysis showed a savings of approximately $22,000 per 100 cases using tranexamic acid. “That doesn’t even factor in the cost savings that would come with avoiding reoperation and shorter ICU lengths of stay,” he pointed out.
“So, our primary conclusion from this study is that there is no evidence to suggest that tranexamic acid has any thrombotic risk in cardiac surgery,” Dr. Myles said.
“Given the high dose and the intense outcome assessments in this study, I think we can be more confident and less concerned about the use of tranexamic acid in terms of thrombotic risk in other surgical settings.” The study was published in The New England Journal of Medicine (2017;376:136-148).